4-Amino-5-hexenoic acid is known in the art as an antiepileptic agent and is described in U.S. Pat. No. 3,960,927. It is also known as vinyl-GABA and is currently available from Merrell Dow Pharmaceuticals, Inc. U.S. Pat. No. 4,621,145 (hereby incorporated by reference) describes one method for synthesizing this compound. The last step in the reaction sequence is depicted below: ##STR1##
In this reaction 5-vinyl-2-pyrrolidinone (structure A) is subjected to an acidic hydrolysis thereby producing the desired compound, 4-amino-5-hexenoic acid (structure B). This acidic hydrolysis is carried out using techniques known in the art. Typically, the 5-vinyl-2-pyrrolidinone is contacted with a strong acid such as hydrochloric acid or trifluoroacteic acid at a temperature above 60.degree. C. in an aqueous solvent system.
Co-pending U.S. patent application Ser. No. 432,707, filed Nov. 7, 1989 (which is hereby incorporated by reference) discloses that vinyl-GABA can be produced by subjecting 5-vinyl-2-pyrrolidinone to a basic hydrolysis as well. This hydrolysis is typically carried out by contacting the 5-vinyl-2-pyrrolidinone with a molar excess of potassium hydroxide. Typically from about 1.1 to about 1.5 equivalents are utilized. The basic hydrolysis is carried out at a temperature ranging from about 60.degree. C. to 140.degree. C. The reaction is typically carried out for a period of time ranging from about 0.5 hours to about 24 hours.
4-Amino-hepta-5,6-dienoic acid is also known in the art as an anti-epileptic agent and is described in U.S. Pat. No. 4,454,156. This compound is also known as allenic-GABA and is under development by Merrell Dow Pharmaceuticals, Inc. Castelhano et al. discloses that allenic-GABA (Structure E) can be produced by a hydrolysis similiar to that discussed above utilizing of 5-allenyl-2-pyrrolidinone (Structure D) as the starting material, J. Am. Chem. Soc. Vol. 106, pages 1877-1879 (1984). This reaction may be depicted as: ##STR2##
U.S. Pat. Nos. 4,621,145 and 4,454,156 disclose that the S-enantiomer of 4-amino-5-hexenoic acid and 4-amino-hepta-5,6-dienoic acid are the preferred isomers.
Recent efforts have focused on developing a commercially viable method for synthesizing the S-enantiomer of these compounds. The following synthetic procedure was developed as depicted by Reaction Scheme I: ##STR3##
In Step A, a racemic pyrrolidinone derivative as described by structure 1 in which A is represented by --CH.dbd.C.dbd.CH.sub.2 or --CH.dbd.CH.sub.2, is acylated with a chiral auxiliary as described by structure 2 in which X and Y are simultaneously represented by the following substituents:
______________________________________ Y X ______________________________________ ##STR4## ##STR5## ##STR6## H ##STR7## H ##STR8## ______________________________________
This acylation reaction produces the disastereomers described by structure 3 and 3' in which A, X, and Y are as defined above. In Step B the disastereomers are separated and the desired S,S isomer depicted by structure 3 is recovered. In Step C, this disastereomer is subjected to a hydrolysis reaction. Depending on the manner in which the hydrolysis is carried out, this reaction produces either the S-pyrroldinone derivative described by structure 4 or the (S)-amino acid derivative described by structure 5 in which A is as defined above.
The acylation reaction of Step A can be carried out using techniques known in the art. Typically the pyrrolidinone derivative of structure 1 is contacted with an approximately equivalent amount of a base such as sodium hydride, butyllithium, lithium diisopropylamine, potassium t-butoxide and potassium carbonate for a period of time ranging from 15 minuites to 3 hours. The reactants are typically contacted at a depressed temperature in the range of -40.degree. C. to 25.degree. C. in an aprotic solvent such as toluene, tetrahydrofuran, toluene/mineral oil, etc. The reaction medium is then warmed to approximately room temperature and an equivalent amount of the chiral auxiliary of structure 2 is added to the reaction. The reactants are typically stirred together for a period of time ranging from 1 minute to 3 hours. The reaction is then quenched by the addition of water and the diastereomers of structure 3 and 3' are recovered by extraction.
In Step B, the diastereomers are separated by techniques known in the art. One suitable method is flash chromatography on silica gel. Suitable eluants include hexane/ethyl acetate, t-butylmethyl ether/hexane and toluene. Another suitable separation method is recrystallization. Suitable solvent systems include polar solvents such as hexane/ethyl acetate or tetrahydrofuran.
In Step C, the (S,S)-diastereomer produced above is subjected to a hydrolysis reaction. Depending upon the manner in which the reaction is carried out, the product will either be the (S)-pyrrolidinone derivative of structure 4 or the (S)-amino acid derivative of structure 5. The pyrrolidinone derivative of Structure 4 can be produced by subjecting the diastereomer to a basic hydrolysis with a weak base such as K.sub.2 CO.sub.3. This hydrolysis is typically carried out in methanol at a temperature range of from 25.degree. C. to 65.degree. C. for a period of time ranging from 1 to 4 hours. The amino acid derivative can be produced by subjecting the diastereomer to a hydrolysis with a stronger base such as potassium hydroxide in a solvent such as water. This hydrolysis is typically carried out at a temperature ranging from 50.degree. C. to 140.degree. C. for a period of time ranging from 1 to 24 hours. Alternatively, the amino acid derivative of structure 5 can be produced via an acidic hydrolysis in which hydrochloric acid is used.
An alternative method of producing either the (S)-pyrrolidinone of structure 4 or the (S)-amino acid of structure 5 is depicted below in Reaction Scheme II: ##STR9##
The initial step is to carry out an acylation reaction between the pyrrolidinone of structure 1 in which A is as defined above and the chiral auxiliary of structure 6 in which X and Y are simultaneously represented by
______________________________________ Y X ______________________________________ ##STR10## H ##STR11## H ##STR12## ______________________________________
This acylation produces the diastereomers of structure 7 and 7'. This acylation can be carried out in the same manner discussed above for Step A of Reaction Scheme I. In Step B these diastereomers are separated and the (S,R)-diastereomer (7') is recovered for further processing. This separation can be carried out in the same manner as the separation of Step B in Reaction Scheme I. In Step C the diastereomer of structure 7 is subjected to a hydrolysis reaction thereby producing the (S)-pyrrolidinone derivative of structure 4 or the amino acid derivative of structure 5. This hydrolysis can be carried out in the same manner as above.
Methods for producing the chiral auxiliaries of structures 2 and 6 are known in the art. Specific methods are disclosed in Examples 1-7. Methods for producing the pyrrolidinones of structure 1 are known in the art.
The following examples are being presented in order to further illustrate the invention. They should not be construed as limiting the invention in any manner.